Tuesday, 22 November 2011

There have been substantial advances in the pharmacotherapy of fibromyalgia (FM), which have occurred in parallel with advances in our understanding of the pathophysiology of FM in the past several years. Consortia of researchers have established a core set of symptom domains, which constitute the condition of FM, including pain, fatigue, sleep and mood disturbance and cognitive dysfunction, which significantly impact a patient’s overall well-being and ability to function. Outcome measures, which assess these domains, both singly and in composite format, are showing increasing reliability to discriminate between the treatment and placebo arms in clinical trials of emerging therapies, which are targeting the pathophysiologic mechanisms of FM. Several different medications, including the serotonin and norepinephrine reuptake inhibitors, duloxetine and milnacipran, and the α2δ modulator, pregabalin, have been approved by the Food and Drug Administration (FDA) for the management of FM, based on their clinically meaningful and durable effect on pain in monotherapy trials. They also have been shown to beneficially effect patient global impression of change, function and variably other key symptom domains, such as fatigue, sleep disturbance and cognition. Other medicines, although they have not gone through the formal approval process, have also shown efficacy in multiple domains of FM. Although combination trials have generally not yet been performed, the combined use of medicines with complementary mechanisms of action is rational, and, when done with appropriate caution, will likely be shown to be safe and well tolerated. Adjunctive therapy with medicines targeted at specific symptom domains, such as sleep, as well as treatments aimed at common co-morbid conditions, such as irritable bowel syndrome, or disease states, such as rheumatoid arthritis, should be considered for the purpose of reducing the patient’s overall symptom burden. Current therapies neither completely treat FM symptoms nor benefit all patients; thus, further research on new therapies with different mechanisms and side-effect profiles is needed.http://www.bprclinrheum.com/article/PIIS1521694211000209/abstract?rss=yes

Fibromyalgia, a condition associated with nervous system dysregulation, is currently a clinical diagnosis based on signs and symptoms. Like many other diseases and conditions, there is no confirmatory test.In this study, 457 patients labeled with fibromyalgia in primary care were re-examined by a rheumatologist, but only 66 percent were diagnosed by the specialist. The authors stated that taking into account the new revised criteria for a diagnosis of fibromyalgia, which incorporate symptoms other than pain as components of fibromyalgia, some patients with predominant mood or psychiatric disorder and less prominent physical symptoms may be misclassified as having fibromyalgia.Even though mood disorder is the strongest associated comorbidity with fibromyalgia, prominent mental illness can masquerade as a pain syndrome and should be recognized. Depression is most often a consequence of inadequately controlled pain.According to the study, of the 155 people who had been misdiagnosed as having fibromyalgia, 65 of them had a current serious mental health/psychiatric problem – although the authors did not specify either the DSM diagnosis or the severity.Of the remaining fibromyalgia patients twelve or 3 percent were considered to have drug seeking behaviors.At entry, 144 (32%) of all patients were on daily opioid medication, with strong opioids such as oxycodone being used by 105 and weak opioids such as tramadol and codeine used by 39. However, of the 302 fibromyalgia patients remaining upon re-examination, 60 were taking strong opioids and 30 weak opioids.The actual prevalence of opioid use by fibromyalgia patients is largely unknown according to the authors. Another study reported that use of any analgesic other than NSAIDS (medications such as aspirin, ibuprofen and naproxen used primarily to treat inflammation, mild to moderate pain) in 52% of patients.

Although opioids are not approved for use in fibromyalgia (hence this is considered off-label use of drug), the FDA has approved three prescription drugs for pain management in fibromyalgia:

Lyrica (preglabin – an anti-seizure drug),

Cymbalta (duloxetine hydrochloride- an antidepressant) and

Savella (milnacipran HCl – an anti-depressant). The anti-depressants are not prescribed for depression however and are generally prescribed in much lower doses than for depression. According to the FDA, studies of these drugs show that a substantial number of people with fibromyalgia received good pain relief, but there were others who don’t benefit.

However there are very few studies of opiod use in fibromyalgia other than for tramadol.In this study, the authors (Fitzcharles MA, Ste-Marie PA, Gamsa A, Ware MA, Shir Y) stated that opioid use was more commonly associated with lower education, unemployment, disability payments, current unstable psychiatric disorder, a history of substance abuse, and previous suicide attempts, but did not break out the differences between the two final groups of patients.According to the Agency for Healthcare Research and Quality, an estimated 12.1 million women age 18 and older reported suffering from chronic pain in 2008 as a result of underlying medical conditions such as chronic fatigue syndrome, endometriosis, fibromyalgia and vulvodynia. Of these women, only 8.7 million reported receiving treatment that year at a total cost of $12.9 billion.

Adrienne Dwello, the guide for the about.com site for fibromyalgia and chronic fatigue syndrome, recently asked patients to comment on their experiences with opioids and garnered 92 comments.

Opioid use, misuse, and abuse in patientslabeled as fibromyalgia.

Source

BACKGROUND: As pain is the cardinal symptom of fibromyalgia, it is logical that treatments directed toward pain relief will be commonly used. Analgesic drug therapy remains the traditional treatment intervention for most chronic pain conditions, with a progressive increased use of opioids in the past 20 years. Concerns about efficacy, risk-benefit ratio, and possible long-term effects of chronic opioid therapy have been raised. There is limited information about opioid treatment in fibromyalgia, with all current guidelines discouraging opioid use.

METHODS: A chart review of all patients referred to a tertiary care pain center clinic with a referring diagnosis of fibromyalgia was conducted to evaluate use of opioid medications.

RESULTS: We have recorded opioid use by 32% of 457 patients referred to a multidisciplinary fibromyalgia clinic, with over two thirds using strong opioids. Opioid use was more commonly associated with lower education, unemployment, disability payments, current unstable psychiatric disorder, a history of substance abuse, and previous suicide attempts.

2011-10-24Thresholds for the diagnosis of fibromyalgia have been lowered, creating more exposure for claims under the accident benefits scheme.
Dr. Arthur Ameis expressed this view during a panel discussion at the Canadian Defence Lawyer's Accident Benefits seminar held in Toronto on Oct. 21.
The American College of Rheumatology suspended the use of the ‘tender point test,' a physical exam to diagnosis fibromyalgia, in 2010 because it felt too many patients were being left out of the diagnosis. Instead, the physical exam was replaced with a 24-question survey about the patients' symptoms.
"So, we are going to see a new wave of fibromyalgia diagnosis because the tender point test is out and you're not even supposed to touch the patient," Ameis said. "The difficulty is that people can go online and read the answers and the diagnosis will happen more and more."http://www.canadianunderwriter.ca/news/thresholds-for-fibromyalgia-and-concussion-diagnosis-lowered/1000643328/

The global market for Fibromyalgia (FM) was valued at $1.7 billion in 2010 and is expected to grow at a Compound Annual Growth Rate (CAGR) of 4.3% to reach $2.4 billion by 2018. The restricted growth in the market is due to the unavailability of approved drugs in the EU and Japan market, expected patent expiry of Cymbalta (2013) and Lyrica (2018) and lack of newer therapies in late stage FM therapeutics pipeline. Currently, FDA (Food and Drug Administration) has approved three drugs for the treatment of FM. Lyrica (pregabalin) was the first drug approved in June 2007 followed by Cymbalta (duloxetine) in June 2008 and Savella (milnacipran) in January 2009. Marketing authorization of these drugs has been rejected by EMEA (European Medical Agency) due low effectiveness and high adverse reactions associated with the drugs. Cymbalta was the first drug to be rejected by EMEA in 2008, followed by Lyrica in 2009 and Savella in 2010. However, increasing prevalence and diagnosis is expected to drive the future FM therapeutics market.http://www.prnewswire.com/news-releases/fibromyalgia-therapeutics---pipeline-assessment-and-market-forecasts-to-2018-132519348.html

In a much larger royal monetization deal, Northwestern University generated $700 million cash in 2007 when it sold a portion of its worldwide royalty interest in the Pfizer drug Lyrica® to Royalty Pharma; net proceeds were placed in the University’s endowment. As part of the deal an undisclosed portion of the payment to Northwestern went to the researchers responsible for the chemical compound that serves as the basis for Lyrica, a drug indicated for fibromyalgia, among other disorders.http://www.genengnews.com/keywordsandtools/print/3/24658/

Thursday, 1 September 2011

Clinical Drug Investigation, 09/01/2011

Branco JC et al. - The effect of pirlindole on sensorimotor performance relevant to driving a motor vehicle is similar to that of placebo, as pirlindole appears to have an activating rather than a sedating antidepressant profile. Because of its specific and reversible inhibition of MAO-A and relatively short elimination half-life, no tyramine or ‘cheese’ effect is likely after short- or long-term administration. The available evidence supports pirlindole as a safe and effective treatment option for the management of depression and fibromyalgia syndrome.

Depression and fibromyalgia syndrome are debilitating chronic conditions that impose a significant burden on individuals, families and society.

Both depression and fibromyalgia have many overlapping symptoms, and antidepressants of several classes are among recommended treatment options for patients with fibromyalgia syndrome.

Pirlindole is a selective and reversible inhibitor of monoamine oxidase (MAO) subtype A (MAO-A) that is approved in some European and non-European countries for the treatment of depression.

The antidepressant efficacy and safety of pirlindole have been demonstrated in a number of placebo- and active comparator-controlled studies and are supported by many years of clinical experience in the treatment of depression.

The drug's efficacy and safety have also been demonstrated, more recently, in the treatment of fibromyalgia syndrome.

Pirlindole has a favourable tolerability profile, with no deleterious effect on cardiovascular dynamics.

Abstract

Objective To describe the diagnosis status and outcome of patients diagnosed with fibromyalgia (FM) by US rheumatologists.

Methods We assessed 1555 patients with FM with detailed outcome questionnaires during 11,006 semiannual observations for up to 11 years. At entry, all patients satisfied American College of Rheumatology preliminary 2010 FM criteria modified for survey research. We determined diagnosis status, rates of improvement, responder subgroups, and standardized mean differences (effect sizes) between start and study completion scores of global well-being, pain, sleep problems, and health related quality of life. (QOL)

Conclusion Although we found no average clinically meaningful improvement in symptom severity overall, 25% had at least moderate improvement of pain over time. The result that emerged from this longitudinal study was one of generally continuing high levels of self-reported symptoms and distress for most patients, but a slight trend toward improvement.

Central neuropathic pain is a heterogeneous group of pain conditions initiated or caused by a primary lesion in the central nervous system. This pain often occurs following spinal cord injury.

Lyrica is currently approved in 110 countries and regions. In the U.S., lyrica capsules CV is approved to treat diabetic nerve pain, pain after shingles, fibromyalgia and partial onset seizures in adults with epilepsy who take one or more drugs for seizures. It is not approved to treat central neuropathic pain in the U.S.

June 23, 2011 -- The last decade brought advances in our understanding of chronic pain, but this has not translated into better treatments yet, an analysis shows. The analysis was published in The Lancet.

It found that treatments for chronic, non-cancer pain such as low back pain, arthritis, headache, and fibromyalgia don't do enough to alleviate pain or restore functioning in the majority of people.
And don't expect any one pill to do the trick, says the report's author, Dennis C. Turk, PhD, an anesthesiologist and pain specialist at the University of Washington in Seattle. "There is this expectation that you will wave a wand and there will be a new pill or new surgery to alleviate your pain, and that is not likely to happen."
"Chronic pain is a complex problem, and the only way to treat it is with a combination of treatments because no one treatment is sufficient," he says. Combination therapy may mean multiple medications or medications plus lifestyle changes, psychological treatments, and/or rehabilitation and physical therapy.
Likening chronic pain to diabetes, Turk says "there are a lot of things to do in addition to medication, as in diabetes, where you also watch your weight and test your urine and blood."
It will involve a more holistic approach, he says. "We have a tendency to try to diagnose people in silos and treat everyone with knee osteoarthritis (OA) the same way," he says. But "we need to treat people as a whole and not just knees." Social, emotional, and environmental factors all play a role in how we experience pain and painful conditions.
One Treatment Not Always EnoughRoger Fillingim, PhD, associate professor in the College of Dentistry at the University of Florida in Gainesville, says that there have been advances in understanding the biology of pain and in awareness of pain as a pressing public health issue in recent years.
But "this hasn't translated into terribly effective treatments of chronic pain, and we will need more multidisciplinary treatments in order to provide more optimal clinical outcome for patients in pain," he says.
The truth is "for many forms of chronic pain, a single treatment is not sufficient to improve quality of life to the point where a patient will be satisfied," he says.
"That pill doesn't exist," he says. "There may be medication that helps alleviate some of the pain, but that needs to be accompanied by other treatments including physical rehabilitation and behavioral or psychological intervention to help people cope with their pain in a more effective manner."
Lesley Arnold MD, a psychiatrist at the University of Cincinnati, takes a more "glass is half-full" view of our accomplishments in treating chronic pain.
"We do have more options today," she says, citing several FDA approvals in recent years for new drugs to treat fibromyalgia and OA. But "we do need more studies of combinations of medications to see what works well together and most importantly, we need studies looking at nondrug therapies."
"We don't have a good way of accessing the central nervous system to tell us why people are in pain," she says.http://www.webmd.com/pain-management/news/20110623/combination-therapy-needed-to-fight-chronic-pain

Saturday, 18 June 2011

Following is an abstract from a published scientific article regarding medical costs associated with fibromyalgia and the impact of a brief multidisciplinary treatment program. The four year medical cost statistics of fibromyalgia compared to control patients in the study group are staggering. The total four-year medical costs for controls in the study were $7774 compared with $15,759 for those with fibromyalgia. Part of the study’s hypothesis included comparing medical costs over a four year period after administration of a cognitive behavior therapy program. The outcome of the study demonstrated that the increased cost in fibromyalgia medical care is related to the severity of symptoms and was not impacted by participation in a brief cognitive behavior therapy program.

STUDY: Direct medical costs in patients with fibromyalgia: Cost of illness and impact of a brief multidisciplinary treatment program.The patients diagnosed with fibromyalgia incur about twice as much direct medical costs than that of non fibromyalgia patients, according to the results of a 4-year study by the Department of Physical Medicine and Rehabilitation at the Mayo Clinic College of Medicine in Rochester, Minnesota. The study was published in the January 2011 issue of the American Journal of Physical Medicine & Rehabilitation.

The objective of the study was to compare the direct medical costs of clinically diagnosed patients with fibromyalgia with the medical costs of matched controls during a 4-yr period and to assess the impact of a fibromyalgia treatment program on healthcare utilization and associated medical costs.The study compared economic outcomes in 87 patients who participated in a fibromyalgia treatment program between 2001 and 2004 and who were local residents for the entire 4-yr period spanning their participation in the program, with age and sex-matched controls. Costs for the 2 yrs before and 2 yrs after program participation were also compared.RESULTS: Four-year medical costs for controls were $7774 compared with $15,759 for those with fibromyalgia. There was no significant change in direct costs after participation in a brief fibromyalgia treatment program. Those with increased symptom severity averaged $2034 higher direct medical costs during the 4-yr period.CONCLUSIONS: Patients with clinically diagnosed fibromyalgia incur direct medical costs about twice that of their matched controls. This increased cost is related to the severity of their symptoms as measured by the Fibromyalgia Impact Questionnaire and was not impacted by participation in a brief cognitive behaviorally based fibromyalgia treatment program.http://www.biorx.net/carolsblog/?m=201106

Recent systematic reviews on psychological therapies of fibromyalgia syndrome (FMS) did not consider hypnosis/guided imagery (H/GI). Therefore we performed a systematic review with meta-analysis of the efficacy of H/GI in FMS.

Six CTs with 239 subjects with a median of 9 (range 7-12) H/GI-sessions were analysed. The median number of patients in the H/GI groups was 20 (range 8-26).
Three studies performed follow-ups. H/GI reduced pain compared to controls at final treatment (SMD -1.17 [95% CI -2.21, -0.13]; p= 0.03.
H/GI did not reduce limitations of HRQOL at final treatment (SMD -0.90 [95% CI -2.55, 0.76]; p=0.29) compared to controls. Effect sizes on fatigue, sleep and depressed mood at final treatment and follow-up and on pain and HRQOL at follow-up were not calculated because of limited data available.
The significant effect on pain at final treatment was associated with low methodological and low treatment quality.

Conclusion:

Further studies with better treatment quality and adequate methodological quality assessing all key domains of FMS are necessary to clarify the efficacy of H/GI in FMS.

TONIX Pharmaceuticals, a specialty pharmaceutical company developing therapies for challenging disorders of the central nervous system, including Fibromyalgia Syndrome (FM) and Post-traumatic Stress Disorder (PTSD), presented sleep EEG (electroencephalogram) findings from a clinical study in which patients with FM were treated with very low dosage (VLD) cyclobenzaprine (CBP) at bedtime. The VLD CBP treated patients showed a decrease in pain, fatigue, tenderness and depressive symptoms and reported fewer of the side effects often associated with daytime CBP at higher doses. In the new findings, VLD CBP treatment improved sleep efficiency and increased the number of nights with reduced rates of EEG Cyclic Alternating Pattern (CAP) sleep types CAPA2 + CAPA3, which are associated with sleep instability and previously were shown to be elevated in FM patients. The findings were the subject of a poster presentation at the Associated Professional Sleep Societies 2011 Anniversary Meeting in Minneapolis, MN.
Dr. Harvey Moldofsky, President and Medical Director, Centre for Sleep and Chronobiology, Toronto, Canada, and lead author of the study, commented, “This study showed that a low dose of cyclobenzaprine taken at bedtime improves the widespread pain and tenderness in patients with fibromyalgia. It also provides a novel algorithm that identifies reductions in a specific EEG pattern of sleep instability that correlate with improvements in the nonrestorative sleep symptoms of fatigue and disturbed mood.”
“These new findings suggest that our technology for bedtime treatment of fibromyalgia with very low dose cyclobenzaprine confers benefits that have been associated with restful or restorative sleep,” stated President Seth Lederman, M.D., Chairman and President of TONIX. About the Study

The study was a randomized, double-blind, placebo-controlled, dose-escalating parallel-design study in 36 patients with FM conducted at two Canadian sites. The study was analyzed with regard to efficacy, safety and tolerability as well as EEG and other parameters assessed during sleep. VLD CBP treated subjects showed significant improvements over eight weeks in pain, fatigue, tenderness, the Hospital Anxiety and Depression Scale (HAD), and sleep efficiency. In addition, VLD CBP was well tolerated, with no adverse events or discontinuations due to adverse events. The sleep EEG data were analyzed for the types of CAP: CAPA1 (associated with sleep stability) and CAPA2 + CAPA3 (usually associated with sleep instability). VLD CBP treatment increased EEG sleep nights with normalized CAPA2+A3, or CAPA2+A3(Norm) ≤ 33%. Increased nights of CAPA2+A3(Norm) ≤ 33% correlated with improvement in fatigue, total HAD score, HAD depression subscore, and self-rated and clinician-rated change in fatigue. In VLD CBP treated subjects, the correlation of increased nights of CAPA2+A3(Norm) ≤ 33% with improvement with FM symptoms is consistent with the hypothesized effects of restorative sleep. The symptomatic benefit may relate to VLD CBP decreasing arousal or alarm signals during sleep. CAPA2+A3(Norm) rate may provide a novel biomarker for assessing treatment effects on nonrestorative sleep and associated subjective somatic and mood symptoms in FM. The full abstract can be found at www.sleepmeeting.org (# 0690).

About TONIX Pharmaceuticals

TONIX Pharmaceuticals is developing new treatments for challenging disorders of the central nervous system. The Company’s most advanced program targets fibromyalgia syndrome based on bedtime treatment with very low dosage cyclobenzaprine. Cyclobenzaprine in higher doses is the active ingredient of U.S. FDA approved muscle relaxants. Based on this foundation, the Company is building a deep and diverse pipeline of high-value medications for other syndromes, disorders and diseases, including post-traumatic stress disorder. For more information, please visit www.tonixpharma.com.

Introduction
Fatigue is one of the most disabling symptoms associated with fibromyalgia that greatly impacts quality of life. Fatigue was assessed as a secondary objective in a 2-phase, 24-week study in outpatients with American College of Rheumatology-defined fibromyalgia.

Methods:
Patients were randomized to duloxetine 60-120 mg/d (N=263) or placebo (N=267) for the 12-week acute phase.
At Week 12, all placebo-treated patients were switched to double-blind treatment with duloxetine for the extension phase. Fatigue was assessed at baseline and every 4 weeks with the Multidimensional Fatigue Inventory (MFI) scales: General Fatigue, Physical Fatigue, Mental Fatigue, Reduced Activity, and Reduced Motivation.
Other assessments that may be associated with fatigue included: Brief Pain Inventory (BPI) average pain, numerical scales to rate anxiety, depressed mood, bothered by sleep difficulties, and musculoskeletal stiffness. Treatment-emergent fatigue-related events were also assessed.
Changes from baseline to Week 12, and from Week 12 to Week 24, were analyzed by mixed-effects model repeated measures analysis.

Conclusions:
Treatment with duloxetine significantly improved multiple dimensions of fatigue in patients with fibromyalgia, and improvement was maintained for up to 24 weeks.Trial Registration: Clinical Trial Registry NCT00673452.

Sunday, 12 June 2011

Fibromyalgia (FM) is a complex syndrome that affects many aspects of the patients life and it is very difficult to evaluate in clinical practice. A recent study has developed the Combined Index of Severity of Fibromyalgia (ICAF), an instrument that evaluates diverse aspects of FM and offers five indices: emotional, physical, active coping, passive coping and total.
The objective of this study is to confirm the structure of the ICAF, check its test-retest reliability, assess its sensitivity to change, and compare the results obtained in a sample of patients with fibromyalgia with another sample of healthy controls.
Methods: A total of 232 patients took part in the study, 228 women and 4 men, with a mean age of 47.73 years of age (SD=8.61) and a time of disease evolution since diagnosis of 4.28 years (SD=4.03). The patients from the FM group completed the ICAF.
Between one and two weeks later, they again attended the clinic and complete the 59 items on the ICAF (retest) and immediately afterwards they began treatment (according to daily clinical practice criteria). A sample of healthy subjects was also studied as a control group: 110 people were included (106 women and 4 men) with a mean age of 46.01 years of age (SD=9.35).
The study was conducted in Spain.
Results: The results obtained suggest that the four-factor model obtained in the previous study adequately fits the data obtained in this study. The test-retest reliability and internal consistency were all significant and show a high degree of correlation for all the factors as well as in overall score.
With the exception of the passive coping factor, all the other scores, including the overall score, were sensitive to change after the therapeutic intervention. The ICAF scores of the patients with fibromyalgia compared with those of the control group were markedly different.
Conclusions: The findings suggest that the ICAF is a valid, reliable, sensitive to change instrument with the added advantage that it offers some additional domains (factors) that provide very valuable information regarding the most delicate aspects of the patient, which must be addressed at the time of treatment in daily clinical practice.

It is not surprising that people with fibromyalgia are interested in alternative medicine approaches.

If there is one area in which conventional medicine often fails, it is in the management of conditions causing chronic pain.

Conventional medicine emphasizes the diagnosis and pharmacologic treatment of various medical conditions based on scientific research. The main philosophy is to identify the cause of the disease and treat it with medicines or surgeries to eliminate the cause. But if someone has chronic pain, does not respond to medications, is not a candidate for a surgical procedure, and has had numerous diagnostic tests that were normal, conventional medicine may be helpless.

Complementary or alternative medicine strategies emphasize the interaction between the body and the mind. The main focus is on maintaining homeostasis, which is the body's natural ability to maintain a stable harmony and balance among its hormones, enzymes, muscles, and organs to prevent disease or to allow the body to heal itself... And an increased number of scientific studies are being published that support the effectiveness of many complementary medicine treatments.

[But in fact] most conditions that doctors treat do not have scientific studies that "prove" a particular treatment is effective. That does not stop us from treating conditions, nor should it. Medical practitioners need to be open-minded. If we always waited for scientific proof, most diseases that exist would not be treated.

Placebo Effect

I remember learning that the placebo effect was “bad.” The placebo effect occurred when a person reported improvement in pain (or other symptoms) after being given a sugar pill instead of the actual drug (or other treatment).

The placebo effect has to be accounted for in any scientific research study because a placebo response does not measure the effect of the drug or treatment being tested. So as not to mistakenly attribute all of the positive benefits to the drug being tested to a placebo effect, research studies are designed to “cancel out” the placebo effect.

Placebo is derived from the Latin word that means “I will please.” It is a positive human response to hopefulness and wanting to get better with a treatment.

Even though the person wasn’t given an actual research drug, she or he felt measurably better simply because of HOPE.

Studies show the placebo effect may happen up to 30% of the time with any treatment. This means 3 of 10 people will feel better when given any type of treatment, with no obvious relationship to the actual treatment.

The placebo effect is a powerful physician “tool” that is not limited to a pill.

Suggestions that a physician makes can have a dramatic effect on how a patient will respond to a particular treatment.

In a study done by Drs. Staats and Hekmat (1998)(1), the role of one’s pain threshold in response to suggestion was examined. Three groups of college students were to place their hands in a tank of ice water. Each group was instructed differently.

• The first group was told “neutral” things: Don’t think about anything, just keep your hand in the water until you need to remove it.

• The second group was told “positive” things: Ice water can improve circulation, strengthen the heart, cleanse the skin cells, and other beneficial effects.

• The third group was told “negative” things: Ice water can be dangerous by causing numbness, decrease in blood flow, tissue damage and hypertension.

All three groups were told to keep their hands immersed until they couldn’t tolerate the pain any more.

Guess what happened? The “positive” group held their hands in longer and reported less anxiety. The “negative group took their hands out much quicker and reported more anxiety. The “neutral” group was in between the other groups.

This study demonstrated how the physician can affect the patient’s response to treatment.
Reassuring, positive words are more likely to increase the therapeutic response – cause a positive placebo response.

I have found much better responses to medications in my patients when I explain what to expect - and tell them the medicines may help but won’t take away all the pain – than if I just gave them the medicines and said, “Take this and let me know if it helps.”

A number of years ago it dawned on me that the placebo response from hopefulness and one’s desire to improve is EXACTLY what we are trying to accomplish in the treatment of chronic pain related to fibromyalgia. We want people to feel better, even if we can’t explain how it happened.

This approach would seem to be one of the major philosophies of complementary medicine - to improve the well-being of body and mind.

With this realization, I’ve washed out all of the negative connotations I learned about placebos from conventional medicine and have become more open-minded. Now one of my philosophies is: Welcome Placebo! We WANT to achieve a positive placebo response.http://www.prohealth.com/library/showarticle.cfm?libid=16313

Clinical trials in chronic pain often collect information about interference with work as answers to component questions of commonly used questionnaires but these data are not normally analysed separately.

Methods: We performed a meta-analysis of individual patient data from four large trials of pregabalin for fibromyalgia lasting 8-14 weeks. We analysed data on interference with work, inferred from answers to component questions of Fibromyalgia Impact Questionnaire (FIQ), Short Form 36 Health Survey, Sheehan Disability Scale, and Multidimensional Assessment of Fatigue, including "How many days in the past week did you miss work, including housework, because of fibromyalgia?"from FIQ.
Analyses were performed according to randomised treatment group (pregabalin 150-600mg daily or placebo), pain improvement (0-10 numerical pain rating scale scores at trial beginning vs. end), and end of trial pain state (100mm visual analogue pain scale [VAS]).

Results: Comparing treatment group average outcomes revealed modest improvement over the duration of the trials, more so with active treatment than with placebo.
For the 'work missed'question from FIQ the change for patients on placebo was from 2.2 (standard deviation [SD] 2.3) days of work lost per week at trial beginning to 1.9 (SD 2.1) days lost at trial end (p<0.01). For patients on 600mg pregabalin the change was from 2.1 (SD 2.2) days to 1.6 (SD 2.0) days (p<0.001).
However, the change in days of work lost was substantial in patients with a good pain response: from 2.0 (SD 2.2) days to 0.97 (SD 1.6) days (p<0.0001) for those experiencing >/=50% pain improvement and from 1.9 (SD 2.2) days to 0.73 (SD 1.4) days (p<0.0001) for those achieving a low level of pain at trial end (<30mm on the VAS). Patients achieving both >/=50% pain improvement and a pain score <30mm on the VAS had the largest improvement, from 2.0 (SD 2.2) days to 0.60 (SD 1.3) days (p<0.0001).
Analysing answers to the other questions yielded qualitatively similar results.

Conclusions: Effective pain treatment goes along with benefit regarding work. A reduction in time off work >1 day per week can be achieved in patients with good pain responses.

Saturday, 21 May 2011

Progenics Pharmaceuticals, Inc. today provided analyses of safety and efficacy endpoints from the 1,034-patient, one-year phase 3 safety study of methylnaltrexone bromide subcutaneous injection in non-malignant pain patients with opioid-induced constipation (OIC). At a fixed dose of 12 mg, the drug was shown to be generally safe and well tolerated, with a safety profile similar to that from a previously reported, shorter-duration efficacy study in non-malignant pain patients. The results are being presented at the annual meeting of the American Pain Society in Austin, TX, May 19-21, 2011.

Patients experienced consistent results across all monthly intervals, and 34.1% of methylnaltrexone 12 mg subcutaneous injections resulted in bowel movements within four hours during the treatment period. In addition, patient subjective assessments showed statistically significant improvements from baseline for a reduction in straining and for the number of bowel movements accompanied by the sensation of complete evacuation.

"This study yielded safety and efficacy data that support the potential utility of subcutaneous methylnaltrexone for use by patients who take opioids for pain over extended periods," said Robert Israel, M.D., senior vice president of medical affairs at Progenics. "We found that the four-hour response rate remained durable over the course of the one-year study period. In addition, the assessed safety of long-term methylnaltrexone use was consistent with previously reported results of the three-month phase 3 efficacy study in non-malignant pain patients with OIC."

The safety study included patients who had a history of chronic, non-malignant pain (including back pain, joint/extremity pain, neurologic/neuropathic pain and fibromyalgia) and who experienced constipation resulting from opioid pain medication use for at least one month prior to screening. Of the 1,034 patients who received at least one dose of methylnaltrexone, 624 patients were treated for six months or more, and 477 completed the 48-week study and post-treatment follow-up periods. Patients took a median of six subcutaneous injections per week of methylnaltrexone 12 mg for up to 48 weeks. There were no observed unexpected safety signals, or cases of gastrointestinal perforation in the study. Pain scores and opioid use data confirmed that methylnaltrexone 12 mg subcutaneous injection did not interfere with analgesia or cause opioid withdrawal symptoms.

These safety data, together with previously announced efficacy data, complete the major datapackages for a supplemental New Drug Application being prepared for submission to the U.S. Food and Drug Administration by the end of June. In this application, Progenics and its commercialization partner, Salix Pharmaceuticals (Nasdaq:SLXP), plan to seek approval for subcutaneous methylnaltrexone in non-malignant pain patients suffering from opioid-induced constipation. Methylnaltrexone currently is approved and marketed as RELISTOR® for the treatment of OIC in patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient.

May 18, 2011 – Pain is a disabling symptom that can occur at any point in the course of an illness. Since pain considerably affects day to day life, its management offers considerable challenge for physicians. Inadequate pain control remains a major problem across the world. Pain relief medications are dominated by NSAIDs followed by opioids. Long acting opioids are used in the relief of moderate to severe pain which require treatment for several days. Oral Long Acting Opioids (LAOs) are also an option to treat acute pain in non-dependant patients. Opioids are prescribed when pain cannot be adequately controlled with an NSAID.

All NSAIDs/Cox-2 inhibitors have cardiovascular and renal side-effects, and the older NSAIDs have severe gastrointestinal ones too. Therefore in cases of acute and chronic opioids continue to be the mainstay of therapy. However, this market is struggling to generate sales growth against a background of weak pipelines and generic competition.

In 2010, the global opioids market was approximately $11.2 billion, representing a compound annual growth rate (CAGR) of 2.4% between 2002 and 2010. By 2017, the global opioids market is forecast to reach $13.2 billion, indicating a CAGR of 2.8% between 2010 and 2017. The market for pain management drugs is focused on enhancement of available dugs with the development of extended release formulations and drug combinations.

In an effort to minimize the risk of misuse, abuse, addiction and overdose opioids are made available through a Risk Evaluation and Mitigation Strategy (REMS) program. In order to ensure that the benefits of the drugs outweigh the risks of use in patients, the FDA had notified opioid drug manufacturers to have REMS. Under this program, pharmacies, distributors, and medical care providers who prescribe to outpatients are required to enroll in the program to prescribe, dispense and distribute opioid drugs.

GBI Research, the leading business intelligence provider, has released its latest research,
“Opioids Market to 2017 - Steady Uptake of Oxycontin and High Incidence Of Diseases Such As Cancer And Arthritis to Drive the Market”, which provides insights into global Opioids market and market forecast until 2017.

Report is built using data and information sourced from proprietary databases, primary and secondary research and in-house analysis by GBI Research’s team of industry experts.

The report provides an in-depth analysis of the top five therapeutic indications for which often opioids are prescribed which includes fibromyalgia, neuropathic pain, cancer pain, osteoarthritis pain, rheumatoid arthritis pain, low back pain and post operative pain. The report also examines the global opioids treatment usage patterns for the covered indication. In addition, the report also includes insights into the opioids R&D pipeline http://www.prlog.org/11496663-opioids-market-to-2017.html

AUSTIN, TX—Initial analysis of the effects of duloxetine vs. placebo in patients with chronic low back pain indicates duloxetine has both brain and behavioral effects in this population, Kevin A. Johnson, of Stanford University School of Medicine, Palo Alto, CA, and colleagues reported during the American Pain Society's 30th Annual Scientific Meeting. These effects were evident on structural MRIs, which indicated changes in gray matter with both duloxetine and placebo, including increases in frontal cortex regions.

The U.S. Food and Drug Administration approved duloxetine, a serotonin-norepinephrine reuptake inhibitor used for a variety of indications—including depression, diabetic peripheral neuropathy, and fibromyalgia—in November 2010 to treat discomfort from lower back pain.The investigators conducted a randomized, double-blind, placebo-controlled crossover study utilizing clinical assessments to examine the effects of duloxetine and placebo. Additionally, MRI was used to detect possible brain effects of duloxetine and placebo. Patients with at least 6 months of back pain (no radicular symptoms), a minimum pain rating of 4 on a scale of 1-10 for two weeks prior to enrollment, and no current use of pain medication (except acetaminophen) were eligible to enter the study.
Patients were randomized to duloxetine 30mg/day for 1 week, followed by 60mg/day for 5 weeks or matching placebo. Clinical assessments occurred at baseline and at Weeks 1, 2, and 6 of each medication period. Week 6 was the crossover point, where patients were switched to duloxetine or placebo. Additional at-home measures were collected. Clinical measures included basic medical assessments, a battery of pain-related questionnaires, and mood and depression ratings. Data have been collected to date on 18 patients.
A significant change in daily pain ratings was found at the end of the duloxetine period, particularly for patients randomized initially to the placebo treatment group (weekly mean P<0.05 at weeks 3 and 6 for duloxetine vs. placebo and P<0.01 at weeks 4 and 6). Most patients (15/18) had minimal to mild depression (Beck Depression Inventory <19) upon study enrollment; at 6 weeks, no significant increases in overall score were noted in the study. Disrupted sleep patterns and loss of energy were the most frequently rated sub-scale items throughout the study. No significant difference between drug and placebo in overall score was noted on the Brief Pain Inventory. On sub-items, significant improvement was seen with duloxetine in worst pain (P=0.009), least pain (P=0.019), average pain (P=0.007), and current pain (P=0.009).
The investigators concluded that given the large individual variability in pain ratings found within an individual treatment period and in response to a particular treatment, accounting for such individual variability may help refine behavioral and neuroanatomical analysis.http://www.clinicaladvisor.com/brain-behavioral-effects-of-duloxetine-observed-in-patients-with-chronic-low-back-pain/article/203418/

May 17 2011
University of Toronto researchers have found that childhood physical abuse is associated with significantly elevated rates of functional somatic syndromes such as chronic fatigue syndrome, fibromyalgia and multiple chemical sensitivities among women.
“Women who reported they had been physically abused as children have twice the odds of chronic fatigue syndrome and multiple chemical sensitivities, and 65 per cent higher odds of fibromyalgia” said lead investigator Professor Esme Fuller-Thomson, who holds the Sandra Rotman Chair at U of T’s Factor-Inwentash Faculty of Social Work and Department of Family and Community Medicine.
“These findings persisted even after controlling for potentially confounding factors such as other adverse childhood experiences, age, race, mental health and adult socioeconomic status.”
The study examined statistics from a regional subsample of the 2005 Canadian Community Health Survey involving 7,342 women, 10 per cent of whom reported being physically abused as children. A minority of women reported they had been diagnosed by a health professional with chronic fatigue syndrome (1.3 percent), fibromyalgia (2.5 percent), or multiple chemical sensitivities (2.7 percent).
Co-author Joanne Sulman, from the Department of Social Work at Mount Sinai, said the research not only points to an association between childhood physical abuse and these disorders, but also explores the contribution of confounding psychosocial factors such as other childhood adversities, adult health behaviours and mental health.
The research will be published in the Journal of Aggression, Maltreatment and Trauma.http://news.bioscholar.com/2011/05/childhood-abuse-linked-to-chronic-fatigue-syndrome-fibromyalgia-in-women.html

Although trazodone is frequently used by fibromyalgia patients, its efficacy on this disease has not been adequately studied. If effective, pregabalin, whose beneficial effects on pain and sleep quality in fibromyalgia have been demonstrated, could complement the antidepressant and anxiolytic effects of trazodone.
The aim of the present study was to assess the effectiveness of trazodone alone and in combination with pregabalin in the treatment of fibromyalgia.

Results:
Treatment with trazodone significantly improved global fibromyalgia severity, sleep quality, and depression, as well as pain interference with daily activities although without showing a direct effect on bodily pain.
After pregabalin combination additional and significant improvements were seen on fibromyalgia severity, depression and pain interference with daily activities, and a decrease in bodily pain was also apparent. During the second phase of the study, only two patients dropped out due to side effects.

Conclusions:
Trazodone significantly improved fibromyalgia severity and associated symptomatology.
Its combination with pregabalin potentiated this improvement and the tolerability of the drugs in association was good.Trial registration: This trial has been registered with ClinicalTrials.gov number NCT-00791739.

AUSTIN, TX—Sodium oxybate was shown to be effective in patients with both moderate to severe fibromyalgia symptoms, according to an analysis presented at the American Pain Society's 30th Annual Scientific Meeting. Sodium oxybate is not currently approved for the treatment of fibromyalgia.

I. Jon Russell, MD, PhD, of the Texas Health Sciences Center, San Antonio, TX, and colleagues from Oregon Health & Science University, Portland, OR, and Jazz Pharmaceuticals, Inc., Palo Alto, CA, analyzed pooled data from two 14-week, Phase 3, double-blind, randomized, placebo-controlled trials to determine the proportions of responders (≥30% reduction on a 0–100mm pain visual analogue scale [VAS]) by moderate (VAS ≥50 to <70) or severe (≥70) pain and by moderate or severe disease, based on clinician global impression of severity (CGI-S) at baseline. A total of 1,121 patients were randomized in the two trials, and were given placebo, sodium oxybate 4.5g or 6g in equal, divided doses at bedtime and 2.5–4 hours later. The data were analyzed by baseline-observation-carried-forward (BOCF) and last-observation-carried-forward (LOCF) methods.
In patients with pain VAS ≥50 to <70, approximately 51% and 54% receiving sodium oxybate 4.5g and 6g, respectively, were responders vs. placebo (29%; P<0.001, LOCF). In patients with pain VAS ≥70, 45% (P=0.013) and 56% (P<0.001), respectively, were responders vs. placebo (33%, LOCF). Subgroup analysis based on CGI-S demonstrated similar efficacy in both dose groups vs. placebo for both the moderately ill/less severe (53% for both doses vs. 35% for placebo; P<0.001, LOCF) and markedly ill/more severe, 41% for sodium oxybate 4.5g (P=0.004) and 57% (P<0.001) for 6 g vs. 25% for placebo(LOCF) groups. BOCF analyses by baseline pain and CGI-S also demonstrated statistically significant efficacy of both sodium oxybate doses vs. placebo (overall P<0.001 for moderately ill/less severe patients and P=0.002 for markedly ill/more severe patinets). The most common adverse events (≥5% in any sodium oxybate treatment group and at least twice the rate of placebo) were nausea, dizziness, vomiting, anxiety, and fatigue.
Dr. Russell et al. concludedthese analyses demonstrate that in patients with fibromyalgia, sodium oxybate demonstrates efficacy for the rduction of pain regardless of whether pain and disease severity were moderate or severe at baseline. Greater proportions of patients having moderate and severe pain, and moderate and severe disease severity achieved ≥30% reduction in pain with sodium oxybate at doses of 4.5g and 6g compared with placebo.http://www.empr.com/sodium-oxybate-reduces-pain-in-patients-with-moderate-and-severe-fibromyalgia-symptoms/article/203417/

AUSTIN, TX—Sustained long-term efficacy and tolerability of milnacipran—in some cases, exceeding three years of continuous usage—is supported in the treatment of patients with fibromyalgia, according to results of an open-label study presented during the American Pain Society's 30th Annual Scientific Meeting.

Fibromyalgia is a chronic disorder characterized by widespread pain and other symptoms that adversely impact function and health-related quality of life. For that reason, durable efficacy is an important treatment goal, noted Lesley Arnold, MD, from the University of Cincinnati College of Medicine, Cincinnati, OH, and colleagues.
To determine long-term efficacy of milnacipran, which is approved for the management of fibromyalgia, treatment effects were evaluated in 1,227 patients in a safety and efficacy study over a period that could exceed three years. Eligible patients were those with fibromyalgia who had successfully completed previous studies of milnacipran. The multicenter, open-label, flexible-dose study comprised a two-week washout period, a two-week dose-escalation period (to milnacipran 100mg/day), an 8-week stable-dose period (at milnacipran 100mg/day), and a flexible-dose period (milnacipran 50–200mg/day) for the remainder of the study. Key efficacy outcomes included 24-hour visual analog scale (VAS) and weekly recall pain (0–100 scale), Patient Global Impression of Change (PGIC), Patient Global Disease Status (PGDS), SF-36 Physical Component Summary (SF-36 PCS), and the Brief Pain Inventory (BPI).
Of the 1,227 patients, 47.7% were considered completers; 206 patients reached the final visit and 379 were enrolled when the study was terminated. Efficacy results were reported as mean changes from study baseline following the two-week washout period. At the final visit, patients treated with milnacipran demonstrated a mean (SEM) improvement from baseline in 24-hour VAS recall pain scores of 23.1 points (1.82) (observed cases). Improvements in VAS weekly recall pain, BPI scores, global status (PGIC, PGDS), and physical function (SF-36 PCS) were all observed with milnacipran treatment.
Over the three-year study, the most common treatment-emergent adverse events were nausea (25.9%), headache (13.4%), hypertension (11.2%), and sinusitis (10.4); 20.9% of patients discontinued the study due to these events, primarily nausea.

17 May 2011 GW Pharmaceuticals, the Cambridge pharma company marketing drugs based on cannabis, has turned a £2.7m loss last time into a net pre-tax profit of £3.1m in the six months to March 31.
The turnround was spurred by an upsurge in total revenues, which increased 45 per cent to £16.6m (H1 2010: £11.4m) including milestone receipts of £5.1m (£nil) and increased Sativex sales of £1.9m (£0.9m).
Cash and short term deposits at period-end increased to £28.3m (£20.4m).
GW’s lead product, Sativex, is a cannabinoid mouth spray identical to whole-plant marijuana in liquid form and was developed for multiple sclerosis patients, who can use it to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms.
Sativex is also being prescribed to alleviate pain due to cancer and has been researched in various models of peripheral and central neuropathic pain.
During the half-year, a licence agreement was signed with Novartis to commercialise Sativex in Australasia, Asia (excluding Japan/China), the Middle East (excluding Israel) and Africa.
It has been recommended for approval in Germany, Italy, Denmark, Sweden, Austria and the Czech Republic. Launches are expected this year in Germany, Denmark and Sweden following launch in Spain in March.
The US is a massive potential market for the company: A Phase III cancer pain programme is underway, fully funded by US partner, Otsuka.

Two Phase IIa clinical trials of novel cannabinoid medicine in diabetes and metabolic disease have also begun.

Positive pre-clinical data in epilepsy, glioma, breast cancer and other conditions continue to be generated as part of Otsuka research collaboration.
Dr Geoffrey Guy, GW’s chairman, said: “GW has delivered another robust set of financial results, with substantially increased revenues yielding a profit for the period and a strong cash position.
“With Sativex now launched in the UK and Spain, an increasing number of additional European approvals and launches for Sativex now expected and the recent agreement with Novartis to commercialise Sativex across a broad region of the world, Sativex should provide GW with a platform for significant growth in the coming years.

“In parallel we have embarked on a substantial Phase III programme for Sativex in cancer pain, a major market opportunity, a Phase II clinical programme for a novel cannabinoid medicine in diabetes and we continue to generate highly promising data in our earlier stage pipeline.
“With regular Sativex launches now taking place, GW has entered a new phase in the evolution of the company and we believe that our prospects for commercial success with Sativex together with a highly promising and maturing pipeline provide confidence for the remainder of 2011 and beyond.”http://www.businessweekly.co.uk/biomedtech-/11836-cannabis-company-up-to-speed-as-cash-starts-to-flow

Acadia Pharmaceuticals Inc. a biopharmaceutical company utilizing innovative technology to fuel drug discovery and clinical development of novel treatments for central nervous system disorders, announced that it has been awarded a grant from the National Institute of Neurological Disorders and Stroke (NINDS), a division of the National Institutes of Health (NIH), for the development of novel Estrogen Receptor beta (ER-beta) agonists for the treatment of neuropathic pain. The grant provides funding of up to $2.4 million and was awarded under the NINDS Fast-Track Small Business Innovative Research Co-operative Programme in Translational Research that supports the identification and preclinical testing of new therapeutics for neurological disorders.

“We are delighted to be awarded this NINDS grant, which allows us to advance our promising ER-beta program in the area of neuropathic pain and provides important recognition of our scientific discoveries,” said Uli Hacksell, PhD, chief executive officer of Acadia. “Our ER-beta compounds also offer the potential for an innovative disease-modifying approach to the treatment of Parkinson's disease, and our initial studies in this area have been supported by grants from The Michael J Fox Foundation.”

Studies have shown that estrogen modulates many cerebral functions such as mental state, mood, cognition and perception of pain. Estrogen stimulates both ER-alpha and ER-beta receptors. Acadia researchers have identified novel and selective ER-beta agonists that may address the symptoms of chronic, inflammatory and neuropathic pain while avoiding the side effects associated with activating ER-alpha receptors. Pursuant to the grant, Acadia will initially examine the efficacy of selected proprietary ER-beta compounds in preclinical models and intends to subsequently conduct preclinical development studies required in support of potential future clinical studies.

Neuropathic pain is a debilitating disorder caused by damage or dysfunction of the nervous system and originates from many diverse sources including diabetic and hereditary neuropathies, herpes, chemotherapy, physical traumas and surgery. Current first-line medications are limited by variable efficacy and adverse effects. There is a major unmet medical need for novel, safe and effective drugs to treat neuropathic pain.

About Me

After service in the British SAS Regiment the author became a physician and then an orthopaedic surgeon.
He has held professorial positions in Canada, Vietnam and the United States, practiced and taught orthopaedic surgery in three continents and in several wars.
He has extensive experience as an expert witness in court. Somewhere along the way, time was found to operate a four hundred acre mixed farm, a one hundred seat restaurant and to obtain a licence as a flying instructor.
The author's books are available from bookstores, the publishers, or from on-line bookstores such as Amazon, Barnes and Noble, and Indigo/Chapters.
http://mclementhall.com